Bruton tyrosine kinase (BTK) is an important member of Tec tyrosine kinase family, which is present in plasmocytes including B cells, mastocytes and macrophages, and plays a decisive role in the B cell receptor (BCR) mediated signal pathway. When BTK is activated by upstream Src family kinases, it phosphorylates downstream phospholipases C (PLC), thereby activating the PI3 and DAG signal pathway. This signal pathway promotes the proliferation, adhesion and survival of cells, and plays an important role in the development of B cell lymphomas.
By inhibiting the activity of BTK, BTK inhibitors can inhibit the proliferation of B cell lymphoma cells, destroy the adhesion of tumor cells, and promote the apoptosis of tumor cells, so that BTK becomes a drug target of interest in B cells-associated cancers, especially B cell lymphoma and leukemia, for example, non-Hodgkin's lymphoma (NHL), chronic lymphocytic leukemia (CLL), and mantle cell lymphoma (MCL), etc. Currently, the only drug with BTK specific inhibition in market is Ibrutinib from Pharmacyclics/JNJ. Ibrutinib is an irreversible small molecule BTK inhibitor, which has significant efficacy on the treatment of MCL, CLL, WM, etc., and is safe. Other BTK inhibitors entering clinical trials for targeting cell lymphomas comprise CC-292 from Celgene company, ACP-196 from Acerta company, ONO-4059 from ONO Company, and BGB-3111 from Beigene Company, and so on.
In addition to anti-B cell lymphomas and anti-leukemia effects, BTK inhibitors can further inhibit the production of B cell autoantibodies and cytokines. Mutations in BTK can lead to a rare genetic disease—X-Linked Agammaglobulinemia (XLA). Because the function of BTK is inhibited in this disease, resulting in inhibition of the production or maturation of B cells and reduction of the circulating antibodies, the patients are prone to serious and even fatal infections. Pre-clinical animal model studies showed that BTK gene-deficient mice can resist to collagen-induced arthritis, and clinical results also demonstrated that Rituxan, an antibody drug for B cell depletion, is efficacious for the treatment of immune disorders. Therefore, the BTK inhibitors can also be used for treating autoimmune-related diseases, such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), anaphylactic diseases (such as, esophagitis, eosoniphilic esophagitis), and so on. Currently, there are not yet a BTK specific inhibitor for use in immune diseases in the market, but several are in clinical stages, for example, CC-292 from Celgene Company, HM-71224 from Hanmi, PRN-1008 from Principia, and a compound from Pharmacyclics.
As BTK plays an important role in a plurality of signaling pathways, the development of BTK inhibitors has attracted attention from many biopharmaceutical companies. A series of patent applications on BTK inhibitors have been disclosed, including WO2007087068, WO2010126960, WO2011019780, WO2011090760, WO2012135801, WO2012158764, WO2013060098, WO2013081016, WO2013010869, WO2013113097, CN103113375, WO2014068527, WO2014125410, WO2014173289, WO2013118986, WO2015017502, WO2015048689, etc. However, there is still a need to develop new compounds with better efficacy. With continuous efforts, the inventor designs a compound having the structure of formula (I), and finds that the compounds having such structure exhibit excellent effects and functions.